I. Field of the Invention
The present invention relates generally to novel proteasome allosteric inhibitors, their use in pharmaceutical compositions, and methods of using the compounds for treating diseases, thereof.
II. Description of Related Art
The enzyme, proteasome, is an essential protease of the ubiquitin-proteasome pathway (UPP) degrading the bulk of intracellular proteins, including vital regulatory factors and damaged polypeptides (Jankowska, et al., 2013). Because of its multifaceted physiological role, which includes regulation of apoptosis, inhibition of proteasome became an attractive intervention to stop cancer (Crawford, et al., 2011). Two FDA-approved proteasome-targeting drugs, bortezomib/Velcade and PR-171/Kyprolis, and several others in clinical trials, compete with proteasome's physiological substrates by blocking its active centers. The inhibition induces apoptosis, as the inactive enzyme fails to degrade IκB and activate NFκB, stabilizes pro-apoptotic proteins, and leaves the cell overloaded with non-degraded polypeptides (Crawford, et al., 2011). These proteasome inhibitors are effective in treatment of blood cancers characterized by high levels of both NFκB and proteasomes (Crawford, et al., 2011; Busse, et al., 2008; Kraus, et al., 2007). Similar up-regulation has been found in subsets of breast cancers (Yamaguchi, et al., 2009; Chen and Madura, 2005), however, there is no evidence of advantage of bortezomib treatment in these or other breast cancer subtypes (Yang, et al., 2006; Engel, et al., 2007). The discovery of the new mechanism of proteasome inhibition introduces a unique opportunity to broaden the list of cancers strongly responding to anti-proteasome therapy.
The proteasome is a complex and diverse enzymatic factory often compared to a molecular organelle (Groll, et al., 2005). All proteasome assemblies contain a tube-shaped 20S (700 kDa) catalytic core (CP) constructed from four hetero heptameric rings. The external α rings form the α face that binds protein complexes regulating the catalysis. The center of the α ring is occupied by an allosterically regulated gate, which provides the passage to the central channel leading to the catalytic chamber built with β-rings (Groll, et al., 2005; Osmulski, et al., 2009). In the Eukaryota there are three pairs of active centers of the N-terminal Thr type that cleave peptide bonds on the carboxyl site of hydrophobic (chymotrypsin-like: ChT-L), basic (trypsin-like: T-L), and acidic (PGPH) amino acids. All clinically relevant proteasome inhibitors target primarily the “workhorse” chymotrypsin-like activity. The 26S assembly, built from CP and at least one 19S regulatory particle (FIG. 1), is the most physiologically significant proteasome since it is the only enzymes in the cell capable of processing protein substrates tagged for degradation by polyubiquitin (Groll, et al., 2005; Madura, 2009). De novo formation of multisubunit RP is a multistep process assisted by several chaperones (Madura, 2009). However, the assembled RP may undergo multiple cycles of association dissociation with CP (Babbitt, et al., 2005). Stability of 26S complex, important for its performance, is regulated by ATP (Liu, et al., 2006), bortezomib (stabilization (Klejinen, et al., 2007)), and by allosteric ligands (Gaczynska, et al., 2003). Other modules binding to the α face include 11S and PA200 activators and PI31 “proteasome inhibitor.” The modules utilize grooves between α subunits for binding to CP, and all except 11S anchor via HbYX (hydrophobic-Tyr-any amino acid) C-terminal motifs (Jankowska, et al., 2013; Smith, 2007). However, new and improved molecules for modulating proteasome function are needed.